Rifamycins, which are a group of macrocylic hydroquinonequinone antibiotics having a close relationship to each other, are described in Antibiotics Annual, 262 (1959), Appl. Microbiol., 9, 325 (1961), and Progr. Ind. Microbiol., 6, 21 (1967).
Rifamycin derivatives have been prepared by the chemical conversion of rifamycin B, which is an antibiotic produced by fermenting Nocardia mediterranei. For example, a number of 3-dialkylaminomethyl derivatives of rifamycin SV can be produced by contacting rifamycin S with dialkylamine and formaldehyde (See, Maggi et al., J. Med. Chem. 8, 790 (1965)). This process is essentially based on the Mannich reaction which has widely been used in organic synthesis for the preparation of amino derivatives of the compounds containing active hydrogen atoms (See, Mannich et al., Arch. Pharm. 250, 647 (1912) and H. O. House, Modern Synthetic Reactions 2nd Ed., pp. 656, (1972), Benjamin Inc.). Under the usually slightly acidic reaction condition, the mechanism of the Mannich reaction is believed to involve electrophilic attack by an iminium salt on the active methylene compound (See, T. F. Cummings et al., J. Org. Chem., 25, 419 (1960). The iminium salt is produced by condensation of alkylamine and formaldehyde as represented by the following equation: ##STR3##
The amine may be of a primary or secondary one; however, a secondary amine is preferably used to avoid any undesirable side reactions. The yield of the Mannich derivatives may differ widely depending on the respective active methylene compounds. For the special case of rifamycins, it has been reported that the yield was about 5 to 72% (See, Maggi et al., J. Med. Chem., 8, 790 (1965)).
Although the Mannich reaction has been previously applied to quinones and hydroquinones (Leffler, M. T. and Hathaway, J., J. Am. Chem. Soc., 70, 3222 (1948)), in the case of the rifamycins only rifamycin S undergoes the Mannich reaction (Maggi et al., J. Med Chem., 8, 790 (1965)). During the reaction, a certain amount of rifamycin SV and alkylaminomethyl rifamycin SV along with the alkylaminomethyl rifamycin S were observed due to the reducing property of the formaldehyde (Maggi et al., J. Med Chem., 8, 790 (1965)). The relatively low yields of this reaction for the special case of rifamycins are, in large part, due to the formation of rifamycin SV which is an inactive form for this reaction. Furthermore, the excess of alkylamine or formaldehyde remaining in a free state may react with the rifamycin S molecule to form other side products. Therefore, in view of the unsatisfactory yield of the alkylaminomethyl rifamycin derivatives based on the Mannich reaction, we have now discovered that the use of pure iminium salt, instead of a mixture of alkylamine and formaldehyde, in obtaining alkylaminomethyl derivatives from rifamycin S results in a better yield.